title: IL-2 contributes to maintaining a balance between CD4+Foxp3+ regulatory T cells and effector CD4+ T cells required for immune control of blood-stage malaria infection.
abstract: To investigate the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in blood-stage malaria, we compared Plasmodium chabaudi AS infection in wild-type (WT) C57BL/6 and transgenic mice overexpressing the transcription factor Foxp3 (Foxp3Tg) and observed that Foxp3Tg mice experienced lethal infection and deficient malaria-specific immune responses. Adoptive transfer of total CD4(+) T cells from Foxp3Tg mice or CD4(+)CD25(+) T cells from WT mice to naive WT recipients confirmed that high numbers of Treg cells compromised immune control of malaria. Transfer of GFP(+)CD4(+)CD25(+) T cells to naive WT recipients together with immunohistochemical staining of spleens from infected WT mice demonstrated that Foxp3(+) Treg cells localized in the T cell area of the spleen. Determination of CD4(+)Foxp3(+) Treg cell responses in the spleen of infected WT mice revealed a significant but transient increase in CD4(+)Foxp3(+) Treg cells early in infection. This was followed by a significant and sustained decrease due to reduced proliferation and apoptosis of CD4(+)Foxp3(+) Treg cells. Importantly, the kinetics of IL-2 secretion by effector CD4(+)Foxp3(-) T cells coincided with changes in CD4(+)Foxp3(+) cells and the differentiation of CD4(+)T-bet(+)IFN-γ(+) cells required for immune control of infection. Administration of the IL-2/anti-IL-2 mAb (clone JES6-1) complex to infected WT mice increased the severity of P. chabaudi AS infection and promoted expansion of Foxp3(+) Treg cells. Collectively, these data demonstrate that the ability to control and eliminate P. chabaudi AS infection is due to a tight balance between natural Treg cells and effector CD4(+) Th1 cells, a balance regulated in part by IL-2.
authors.affiliation: Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, H3G 1A4 Canada.
authors.forename: Floriana
authors.initials: F
authors.lastname: Berretta
authors.forename: Jessica
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.forename: Mary M
authors.initials: MM
authors.lastname: Stevenson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000276:immunology; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016788:Plasmodium chabaudi / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma